Administration Of Fusaric Acid Research Articles

Fusaric acid (FA) protects heart failure induced by isoproterenol (ISP) in mice through fibrosis prevention via TGF-β1/SMADs and PI3K/AKT signaling pathways

Fusaric acid (FA) is a novel compound derived from a class of nicotinic acid derivatives, exhibiting activity against cancers. However, its role in regulating cardiac injury is limited. Our study was aimed to investigate the role and the underlying molecular mechanism of FA in heart fibrosis and hypertrophy. Isoproterenol (ISP) was used to induce cardiac fibrosis and hypertrophy in vitro and in vivo. FA administration ameliorated hypertrophy by reducing atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β −myosin heavy chain (β-MHC) in vitro and in vivo. Additionally, FA reduced collagen accumulation and fibrosis-related signals, including α- smooth muscle actin (α-SMA), Collagen type I and Collagen type III. Transforming growth factor-β1 (TGF-β1)/SMADs and mitogen-activated protein kinases (MAPKs), including p38, extracellular signal regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), signalling pathways were highly activated for ISP induction, which were prevented due to FA administration. Further, FA suppressed ISP-induced PI3K/AKT activity in a dose dependent manner. Of note, FA-reduced MAPKs phosphorylation was associated with phosphoinositide 3-Kinase (PI3K)/Protein kinase B (AKT) activity caused by ISP. However, PI3K/AKT activation showed no effects on TGF-β1/SMADs expression in FA-treated cells after ISP exposure. Together, FA might be an effective candidate agent for preventing cardiac fibrosis by modulating TGF-β1/SMADs and PI3K/AKT signalling pathways.

Fusaric Acid and Modification of the Subchronic Toxicity to Rats of Fumonisins in F. moniliforme Culture Material

Fumonisins and fusaric acid (FA) are mycotoxins produced by Fusarium moniliforme and other Fusarium which grow on corn. Fumonisins cause animal toxicities associated with F. moniliforme and, like F. moniliforme, they are suspected human oesophageal carcinogens. Toxic synergism was obtained by simultaneous administration of FA and fumonisin B 1 to chicks in ovo. To determine the effect of FA on in vivo toxicity of F. moniliforme culture material (CM), male rats (12 groups, n=5/group) were fed diets containing 0.025, 0.10 or 2.5% CM (providing dietary levels of 3.4, 18.4 or 437 ppm fumonisins, respectively) to which, at each CM level, 0, 20, 100 or 400 ppm FA were added. Additionally, an FA control group was fed 400 ppm FA only and an untreated control group was given neither FA nor culture material. Apoptosis and other effects consistent with those caused by fumonisins were present in the kidneys of animals fed 0.025% or more CM and in the livers of animals fed 2.5% CM. FA was without effect. No differences between the untreated and FA control groups were noted and no differences among the four groups (0–400 ppm FA) fed 0.025% CM, the four groups fed 0.10% CM or the four groups fed 2.5% CM were apparent. Thus, FA exerted no synergistic, additive or antagonistic effects on the subchronic in vivo toxicity of fumonisin-producing F. moniliforme.

Mechanism of suppressed renin-angiotensin system in spontaneously hypertensive rat (SHR).

Plasma renin concentration (PRC) of SHR decreased with the elevation of blood pressure. In addition in vitro study of basal renin release from kidney slices obtained from SHR produced similar results. However kidney renin activity and total renin content in kidney of SHR were not less than those of Wistar rats. These results indicate that the decreased renin release from kidney might be responsible for the suppression of renin-angiotensin system of SHR after the development of hypertension. Administration of fusaric acid, a dopamine-beta-hydroxylase inhibitor markedly decreased urinary excretion of catecholamine and prostaglandin E in both SHR and Wistar rat and abolished the development of hypertension in SHR. PRC of SHR which became normotensive by fusaric acid administration (normotensive SHR), increased up to the level of control Wistar rats. Therefore suppressed renin-angiotensin system was not observed in normotensive SHR. Nevertheless basal renin release from kidney slices obtained from normotensive SHR was still less than that from control Wistar rats. As urinary catecholamine and prostaglandin E excretion were decreased by fusaric acid administration, these well-known renin stimulators could not be responsible for the reversal of suppressed renin-angiotensin system in normotensive SHR. Rather decreased arterial blood pressure in normotensive SHR lowered renal perfusion pressure, and led to the stimulation of renin release up to the levels of control Wistar rats by the activation of renal arteriolar baroreceptors.

24-hour rhythm of human plasma noradrenaline and the effect of fusaric acid, a dopamine-beta-hydroxylase inhibitor.

A 24-hour of basal noradrenaline (NA) levels in normal human plasma in the supine position was observed; higher NA levels during daytime and lower NA levels at night, especially early in the morning. This pattern of the 24-hour rhythm of plasma NA levels was similar to that of serum dopamine-beta-hydroxylase (DBH) levels. After oral administration of fusaric acid, a DBH inhibitor, the rhythm changed, and plasma NA levels increased at 3 h and returned to the initial level at 23 h. In contrast, plasma DBH activity was markedly inhibited during 23 h after fusaric acid administration.

Inhibition of human serum dopamine -hydroxylase after the oral administration of fusaric acid.

Die Dopamin-β-Hydroxylase-Aktivitat im menschlichen Serum wurde nach der oralen Zufuhr von Fusarinsaure (50–300 mg) stark gehemmt.

Inhibition of dopamine β-hydroxylase by fusaric acid (5-butylpicolinic acid) in vitro and in vivo

Fusaric acid (5-butylpicolinic acid) was found to be a potent inhibitor of dopamine β-hydroxylase in vitro and in vivo. Fusaric acid inhibited the enzyme by 50 per cent at a concentration of 3 × 10 −8 M. Kinetic studies with purified dopamine β-hydroxylase showed that the inhibition by fusaric acid was of the uncompetitive type with the substrate and of the mixed type with a cofactor, ascorbic acid. Fusaric acid lowered endogenous levels of norepinephrine and epinephrine in brain, heart, spleen and adrenal glands. Maximum depletion of norepinephrine and epinephrine was observed between 3 and 6 hr after the administration of fusaric acid. Since dopamine β-hydroxylase activity in adrenal medulla was found to be inhibited in vivo after the administration of fusaric acid, the decrease in the catecholamine levels is attributed to the inhibition of norepinephrine synthesis at the dopamine β-hydroxylase stage.